RareFold-Agent: Autonomous Exploration of Noncanonical Amino Acid Spaces

ABSTRACT

While tools like AlphaFold have mastered the 20 canonical amino acids, expanding structural prediction to include noncanonical amino acids (NCAAs) remains a manual, computationally intensive process. We propose RareFold-Agent, an autonomous system that dynamically updates structural frames and manages Multiple Sequence Alignment (MSA) queries for 29 novel NCAAs. The agent intelligently masks non-standard residues during MSA searches and iteratively refines structural coordinates to accommodate bulky or chemically modified sidechains. This autonomous pipeline allows researchers to explore entirely new functional protein spaces without deep expertise in structural bioinformatics.